Transcriptomic profiling and quantitative high-throughput (qHTS) drug screening of CDH1 deficient hereditary diffuse gastric cancer (HDGC) cells identify treatment leads for familial gastric cancer

Chen, Ina; Mathews-Greiner, Lesley; Li, Dandan; Abisoye-Ogunniyan, Abisola; Ray, Satyajit; Bian, Yansong; Shukla, Vivek; Zhang, Xiaohu; Guha, Raj; Thomas, Craig J.; Gryder, Berkley E.; Zacharia, Athina; Beane, Joal D.; Ravichandran, Sarangan; Ferrer, Marc; Rudloff, Udo

doi:10.1186/s12967-017-1197-5

Cited by 13 publications

(14 citation statements)

References 31 publications

(63 reference statements)

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“…Furthermore, Ping et al ( 37 ) reported that decreased CXCL12 in the tumor microenvironment may facilitate lymphoid malignant cells metastasis by limiting the interactions between malignant cells and surrounding cells in lymphocytic leukemia. CDH1 , as a member of the cadherin superfamily, may serve a critical role in apoptotic process and cell-cell adhesion ( 38 ). A previous study demonstrated that CDH1 expression was lower in gastric cancer and this decrease contributed to intestinal-type gastric carcinogenesis ( 39 ).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics and functional analyses of key genes and pathways in human clear cell renal cell carcinoma

et al. 2018

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Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. The present study was conducted to explore the mechanisms and identify the potential target genes for ccRCC using bioinformatics analysis. The microarray data of GSE15641 were screened on Gene-Cloud of Biotechnology Information (GCBI). A total of 32 ccRCC samples and 23 normal kidney samples were used to identify differentially expressed genes (DEGs) between them. Subsequently, the clustering analysis and functional enrichment analysis of these DEGs were performed, followed by protein-protein interaction (PPI) network, and pathway relation network. Additionally, the most significant module based on PPI network was selected, and the genes in the module were identified as hub genes. Furthermore, transcriptional level, translational level and survival analyses of hub genes were performed to verify the results. A total of 805 genes, 403 upregulated and 402 downregulated, were differentially expressed in ccRCC samples compared with normal controls. The subsequent bioinformatics analysis indicated that the small molecule metabolic process and the metabolic pathway were significantly enriched. A total of 7 genes, including membrane metallo-endopeptidase (MME), albumin (ALB), cadherin 1 (CDH1), prominin 1 (ROM1), chemokine (C-X-C motif) ligand 12 (CXCL12), protein tyrosine phosphatase receptor type C (PTPRC) and intercellular adhesion molecule 1 (ICAM1) were identified as hub genes. In brief, the present study indicated that these candidate genes and pathways may aid in deciphering the molecular mechanisms underlying the development of ccRCC, and may be used as therapeutic targets and diagnostic biomarkers of ccRCC.

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Section: Discussionmentioning

confidence: 99%

Bioinformatics and functional analyses of key genes and pathways in human clear cell renal cell carcinoma

et al. 2018

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“…c.1380delA CDH1mutant cells were selectively sensitive to inhibition of the EGFR effectors PI3K, mTOR, MEK, c-Src, FAK, and TOPO2 inhibition. The drug phenotype overlapped with the top two signaling networks found enriched by Meta-Core analysis in c.1380delA cells [12]. The highest-ranking network predicted to be enriched in c.1380delA cells included a number of signaling regulators of the enriched epidermal growth factor receptor signaling pathway or inositol triphosphate (IP3)/diacylglyercol (DAG) signaling which directly or indirectly overlapped with the drug phenotype of enhanced sensitivity against MEK, mTOR, FAK, or PKC activity anti-PKC, c-Src kinase, and FAK activity.…”

Section: High-throughput Drug Screening In Cell-based Models Of Hdgcmentioning

confidence: 95%

“…As no effective systemic therapies are available for HDGC, an initial broad evaluation of potential drug targets is desirable. Our group conducted a differential high-throughput drug screen in gastric cancer cells derived from a stage IV HDGC patient with a truncating c.1380delA CDH1 germline mutation and gastric cancer cells derived from a liver lesion of a gastric cancer patient with wild type CDH1 [12]. The drug library utilized for screening was enriched for oncology compounds and contained multiple compounds per class to detect class effects.…”

Section: High-throughput Drug Screening In Cell-based Models Of Hdgcmentioning

confidence: 99%

“…Quantitative high-throughput drug screening of MCF10A mammary epithelial cells vs isogenic CDH1 −/− MCF10A cells and hereditary c.1380del CDH1 gastric cancer cells vs sporadic CDH1 wild type SB.msgc-1 cells. Listed are vulnerabilities selective in CDH1 −/− -mutant MCF10A and c.1380del CDH1 cells, shared drug classes are highlighted in italics Active in both c.1380delA CDH1 mutant hereditary SB.mhdgc-1 and control CDH1 wild type SB.msgc-1 gastric cancer cells CDH1 MCF10A (−/−) [13] CDH1 MCF10A (−/−) [13] c.1380delA CDH1 HDGC [12] c.1380delA CDH1 HDGC [ and drug phenotype and enriched gene expression aberrations in c.1380delA HDGC cells. Differences in lineage and evolvement of screened cells, like pre-neoplastic primary mammary epithelial MCF10A cells versus metastatic cells derived from the ascites of a CDH1 germline mutation carrier with stage IV gastric cancer, or different coverages of the used drug libraries, might explain differences in observed drug phenotype like lack of HDAC inhibition, anti-Bcl2, and anti-XIAP sensitivity in the c.1380delA CDH1 cells or lack of sensitivity to MEK inhibition in the CDH1 −/− null MCF10A cells.…”

Section: Table 1 Drug Sensitivities Derived From In Vitro Models Of Hdgcmentioning

confidence: 99%

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Merging perspectives: genotype‐directed molecular therapy for hereditary diffuse gastric cancer (HDGC) and E‐cadherin–EGFR crosstalk

Li¹,

Rudloff³

2018

Clinical & Translational Med

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Hereditary diffuse gastric cancer is a cancer predisposition syndrome associated with germline mutations of the E-cadherin gene (CDH1; NM_004360). Male CDH1 germline mutation carriers have by the age of 80 years an estimated 70% cumulative incidence of gastric cancer, females of 56% for gastric and of 42% for lobular breast cancer. Metastatic HDGC has a poor prognosis which is worse than for sporadic gastric cancer. To date, there have been no treatment options described tailored to this molecular subtype of gastric cancer. Here we review recent differential drug screening and gene expression results in c.1380del CDH1-mutant HDGC cells which identified drug classes targeting PI3K (phosphoinositide 3-kinase), MEK (mitogen-activated protein kinase), FAK (focal adhesion kinase), PKC (protein kinase C), and TOPO2 (topoisomerase II) as selectively more effective in cells with defective CDH1 function. ERK1-ERK2 (extracellular signal regulated kinase) signaling measured as top enriched network in c.1380delA CDH1-mutant cells. We compared these findings to synthetic lethality and pharmacological screening results in isogenic CDH1 −/− MCF10A mammary epithelial cells with and without CDH1 expression and current knowledge of E-cadherin/catenin–EGFR cross-talk, and suggest different rationales how loss of E-cadherin function activates PI3K, mTOR, EGFR, or FAK signaling. These leads represent molecularly selected treatment options tailored to the treatment of CDH1-deficient familial gastric cancer.

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“…The incidence of gastric carcinoma (GC) varies between males and females [1,2], among individual nations and regions of the world [3,4], and is associated with infectious [5][6][7], environmental [8,9], and genetic [10,11] factors.…”

Section: Introductionmentioning

confidence: 99%

Higher risk of gastric cancer among immigrants to Ontario: a population-based matched cohort study with over 2 million individuals

et al. 2017

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Transcriptomic profiling and quantitative high-throughput (qHTS) drug screening of CDH1 deficient hereditary diffuse gastric cancer (HDGC) cells identify treatment leads for familial gastric cancer

Cited by 13 publications

References 31 publications

Bioinformatics and functional analyses of key genes and pathways in human clear cell renal cell carcinoma

Bioinformatics and functional analyses of key genes and pathways in human clear cell renal cell carcinoma

Merging perspectives: genotype‐directed molecular therapy for hereditary diffuse gastric cancer (HDGC) and E‐cadherin–EGFR crosstalk

Higher risk of gastric cancer among immigrants to Ontario: a population-based matched cohort study with over 2 million individuals

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